Objective: As thionamide is associated with various adverse effects, we reevaluated the practical efficacy of potassium iodide (KI) therapy for Graves' hyperthyroidism (GD).
Methods: We administered KI (mainly 100 mg/day) to 324 untreated GD patients, and added methimazole (MMI) only to those remaining thyrotoxic even at 200 mg/day. When the patient became hypothyroid, MMI if taken was stopped, then levothyroxine (LT4) was added without reducing the KI dose. Radioactive iodine (RI) therapy or thyroidectomy was performed whenever required. We evaluated the early effects of KI at 2-4 weeks, and followed patients for 2 years.
Results: At 2 weeks, serum thyroid hormone decreased in all 324 patients. At 4 weeks, fT4, fT3, and both fT4 and fT3 levels became normal or low in 74.7%, 50.6%, and 50.6%, respectively. In a cross-sectional survey over 2-years, GD was well-controlled with KI or KI+LT4 (KI-effective) in >50% of patients at all time points. Among 288 patients followed for 2 years, 42.7% remained 'KI-effective' throughout 2 years (KI Group), 30.9% were well-controlled with additional MMI given for 1-24 months, and 26.4% were successfully treated with ablative therapy (mainly RI). Among 'KI-effective' patients at 4 weeks, 76.5% were classified into KI Group. No patients experienced adverse effects of KI.
Conclusion: KI therapy was useful in the treatment of GD. A sufficient dose of KI was effective in >50% of GD patients from 4 weeks to 2 years, and 42.7% (76.5% of 'KI effective' patients at 4 weeks) remained 'KI-effective' throughout 2 years.
{"title":"Graves' hyperthyroidism treated with potassium iodide: early response and 2 years of follow-up.","authors":"Megumi Fujikawa, Ken Okamura","doi":"10.1530/ETJ-24-0085","DOIUrl":"https://doi.org/10.1530/ETJ-24-0085","url":null,"abstract":"<p><strong>Objective: </strong>As thionamide is associated with various adverse effects, we reevaluated the practical efficacy of potassium iodide (KI) therapy for Graves' hyperthyroidism (GD).</p><p><strong>Methods: </strong>We administered KI (mainly 100 mg/day) to 324 untreated GD patients, and added methimazole (MMI) only to those remaining thyrotoxic even at 200 mg/day. When the patient became hypothyroid, MMI if taken was stopped, then levothyroxine (LT4) was added without reducing the KI dose. Radioactive iodine (RI) therapy or thyroidectomy was performed whenever required. We evaluated the early effects of KI at 2-4 weeks, and followed patients for 2 years.</p><p><strong>Results: </strong>At 2 weeks, serum thyroid hormone decreased in all 324 patients. At 4 weeks, fT4, fT3, and both fT4 and fT3 levels became normal or low in 74.7%, 50.6%, and 50.6%, respectively. In a cross-sectional survey over 2-years, GD was well-controlled with KI or KI+LT4 (KI-effective) in >50% of patients at all time points. Among 288 patients followed for 2 years, 42.7% remained 'KI-effective' throughout 2 years (KI Group), 30.9% were well-controlled with additional MMI given for 1-24 months, and 26.4% were successfully treated with ablative therapy (mainly RI). Among 'KI-effective' patients at 4 weeks, 76.5% were classified into KI Group. No patients experienced adverse effects of KI.</p><p><strong>Conclusion: </strong>KI therapy was useful in the treatment of GD. A sufficient dose of KI was effective in >50% of GD patients from 4 weeks to 2 years, and 42.7% (76.5% of 'KI effective' patients at 4 weeks) remained 'KI-effective' throughout 2 years.</p>","PeriodicalId":12159,"journal":{"name":"European Thyroid Journal","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Thyroid eye disease (TED) is an autoimmune orbital disease, with intravenous glucocorticoid (IVGC) therapy as the first-line treatment. Due to uncertain response rates and possible side effects, various prediction models have been developed to predict IVGC therapy outcomes.
Methods: A thorough search was conducted in PubMed, Embase, and Web of Science databases. Data extraction included publication details, prediction model content, and performance. Statistical analysis was performed using R software, including heterogeneity evaluation, publication bias, subgroup analysis, and sensitivity analysis. Forest plots were utilized for result visualization.
Results: Of the 12 eligible studies, 47 prediction models were extracted. All included studies exhibited a low-to-moderate risk of bias. The pooled area under the receiver operating characteristic curve (AUC) and the combined sensitivity and specificity for the models were 0.81, 0.75, and 0.79, respectively. In view of heterogeneity, multiple meta-regression and subgroup analysis were conducted, which showed that marker and modeling types may be the possible causes of heterogeneity (P < 0.001). Notably, imaging metrics alone (AUC = 0.81) or clinical characteristics combined with other markers (AUC = 0.87), incorporating with multivariate regression (AUC = 0.84) or radiomics analysis (AUC = 0.91), yielded robust and reliable prediction outcomes.
Conclusion: This meta-analysis comprehensively reviews the predictive models for IVGC therapy response in TED. It underscores that integrating clinical characteristics with laboratory or imaging indicators and employing advanced techniques like multivariate regression or radiomics analysis significantly enhance the efficacy of prediction. Our research findings offer valuable insights that can guide future studies on prediction models for IVGC therapy in TED.
{"title":"Prediction models of intravenous glucocorticoids therapy response in thyroid eye disease.","authors":"Haiyang Zhang, Shuo Wu, Shuyu Hu, Xianqun Fan, Xuefei Song, Tienan Feng, Huifang Zhou","doi":"10.1530/ETJ-24-0122","DOIUrl":"10.1530/ETJ-24-0122","url":null,"abstract":"<p><strong>Background: </strong>Thyroid eye disease (TED) is an autoimmune orbital disease, with intravenous glucocorticoid (IVGC) therapy as the first-line treatment. Due to uncertain response rates and possible side effects, various prediction models have been developed to predict IVGC therapy outcomes.</p><p><strong>Methods: </strong>A thorough search was conducted in PubMed, Embase, and Web of Science databases. Data extraction included publication details, prediction model content, and performance. Statistical analysis was performed using R software, including heterogeneity evaluation, publication bias, subgroup analysis, and sensitivity analysis. Forest plots were utilized for result visualization.</p><p><strong>Results: </strong>Of the 12 eligible studies, 47 prediction models were extracted. All included studies exhibited a low-to-moderate risk of bias. The pooled area under the receiver operating characteristic curve (AUC) and the combined sensitivity and specificity for the models were 0.81, 0.75, and 0.79, respectively. In view of heterogeneity, multiple meta-regression and subgroup analysis were conducted, which showed that marker and modeling types may be the possible causes of heterogeneity (P < 0.001). Notably, imaging metrics alone (AUC = 0.81) or clinical characteristics combined with other markers (AUC = 0.87), incorporating with multivariate regression (AUC = 0.84) or radiomics analysis (AUC = 0.91), yielded robust and reliable prediction outcomes.</p><p><strong>Conclusion: </strong>This meta-analysis comprehensively reviews the predictive models for IVGC therapy response in TED. It underscores that integrating clinical characteristics with laboratory or imaging indicators and employing advanced techniques like multivariate regression or radiomics analysis significantly enhance the efficacy of prediction. Our research findings offer valuable insights that can guide future studies on prediction models for IVGC therapy in TED.</p>","PeriodicalId":12159,"journal":{"name":"European Thyroid Journal","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11378126/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-23Print Date: 2024-08-01DOI: 10.1530/ETJ-24-0028
Fabio Hecht, Laura Valerio, Carlos Frederico Lima Gonçalves, Marylin Harinquet, Rabii Ameziane El Hassani, Denise P Carvalho, Stephane Koundrioukoff, Jean-Charles Cadoret, Corinne Dupuy
Objective: Ionizing radiation generates genomic instability by promoting the accumulation of chromosomal rearrangements. The oncogenic translocation RET/PTC1 is present in more than 70% of radiation-induced thyroid cancers. Both RET and CCDC6, the genes implicated in RET/PTC1, are found within common fragile sites - chromosomal regions prone to DNA breakage during slight replication stress. Given that irradiated cells become more susceptible to genomic destabilization due to the accumulation of replication-stress-related double-strand breaks (DSBs), we explored whether RET and CCDC6 exhibit DNA breakage under replicative stress several days post-irradiation of thyroid cells.
Methods: We analyzed the dynamic of DNA replication in human thyroid epithelial cells (HThy-ori-3.1) 4 days post a 5-Gy exposure using molecular DNA combing. The DNA replication schedule was evaluated through replication-timing experiments. We implemented a ChIP-qPCR assay to determine whether the RET and CCDC6 genes break following irradiation.
Results: Our study indicates that replicative stress, occurring several days post-irradiation in thyroid cells, primarily causes DSBs in the RET gene. We discovered that both the RET and CCDC6 genes undergo late replication in thyroid cells. However, only RET's replication rate is notably delayed after irradiation.
Conclusion: The findings suggest that post-irradiation in the RET gene causes a breakage in the replication fork, which could potentially invade another genomic area, including CCDC6. As a result, this could greatly contribute to the high prevalence of chromosomal RET/PTC rearrangements seen in patients exposed to external radiation.
目的:电离辐射通过促进染色体重排的积累而产生基因组不稳定性。70%以上由辐射诱发的甲状腺癌存在致癌易位 RET/PTC1。与 RET/PTC1 有关的基因 RET 和 CCDC6 都位于常见的脆性位点内,即在轻微的复制压力下容易发生 DNA 断裂的染色体区域。鉴于辐照细胞因复制应激相关双链断裂(DSB)的积累而更易发生基因组不稳定,我们探讨了甲状腺细胞辐照几天后,RET和CCDC6是否会在复制应激下发生DNA断裂:我们利用分子 DNA 梳理技术分析了人类甲状腺上皮细胞(HThy-ori-3.1)在 5-Gy 照射 4 天后的 DNA 复制动态。通过复制时间实验评估了 DNA 复制时间表。我们采用了 ChIP-qPCR 分析法来确定辐照后 RET 和 CCDC6 基因是否断裂:结果:我们的研究表明,甲状腺细胞在辐照后数天出现的复制应激主要导致 RET 基因中的 DSB。我们发现,甲状腺细胞中的 RET 基因和 CCDC6 基因都会发生晚期复制。然而,只有RET的复制速度在辐照后明显延迟:结论:研究结果表明,RET基因在辐照后会导致复制叉断裂,从而有可能侵入另一个基因组区域,包括CCDC6。结论:研究结果表明,辐照后 RET 基因会导致复制叉断裂,从而有可能侵入另一个基因组区域,包括 CCDC6,因此,这在很大程度上导致了外照射患者染色体 RET/PTC 重排的高发病率。
{"title":"A post-irradiation-induced replication stress promotes RET proto-oncogene breakage.","authors":"Fabio Hecht, Laura Valerio, Carlos Frederico Lima Gonçalves, Marylin Harinquet, Rabii Ameziane El Hassani, Denise P Carvalho, Stephane Koundrioukoff, Jean-Charles Cadoret, Corinne Dupuy","doi":"10.1530/ETJ-24-0028","DOIUrl":"10.1530/ETJ-24-0028","url":null,"abstract":"<p><strong>Objective: </strong>Ionizing radiation generates genomic instability by promoting the accumulation of chromosomal rearrangements. The oncogenic translocation RET/PTC1 is present in more than 70% of radiation-induced thyroid cancers. Both RET and CCDC6, the genes implicated in RET/PTC1, are found within common fragile sites - chromosomal regions prone to DNA breakage during slight replication stress. Given that irradiated cells become more susceptible to genomic destabilization due to the accumulation of replication-stress-related double-strand breaks (DSBs), we explored whether RET and CCDC6 exhibit DNA breakage under replicative stress several days post-irradiation of thyroid cells.</p><p><strong>Methods: </strong>We analyzed the dynamic of DNA replication in human thyroid epithelial cells (HThy-ori-3.1) 4 days post a 5-Gy exposure using molecular DNA combing. The DNA replication schedule was evaluated through replication-timing experiments. We implemented a ChIP-qPCR assay to determine whether the RET and CCDC6 genes break following irradiation.</p><p><strong>Results: </strong>Our study indicates that replicative stress, occurring several days post-irradiation in thyroid cells, primarily causes DSBs in the RET gene. We discovered that both the RET and CCDC6 genes undergo late replication in thyroid cells. However, only RET's replication rate is notably delayed after irradiation.</p><p><strong>Conclusion: </strong>The findings suggest that post-irradiation in the RET gene causes a breakage in the replication fork, which could potentially invade another genomic area, including CCDC6. As a result, this could greatly contribute to the high prevalence of chromosomal RET/PTC rearrangements seen in patients exposed to external radiation.</p>","PeriodicalId":12159,"journal":{"name":"European Thyroid Journal","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11378124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141758068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-19Print Date: 2024-08-01DOI: 10.1530/ETJ-24-0153
Pepijn van Houten, James Nagarajah, Janneke E W Walraven, Martin Jaeger, Adriana C H van Engen-van Grunsven, Johannes W Smit, Romana T Netea-Maier
Objective: Patients with non-medullary thyroid carcinoma (NMTC) that are refractory to radioactive iodine (RAI) have a poor prognosis. Strategies for restoring the ability to take up iodine, so-called redifferentiation, are promising but not suitable for all patients. Preclinical studies, in human cell lines just as in a murine model, have shown that the cardiac glycoside digoxin restored RAI uptake. This prospective single-center open-label study aimed to investigate whether treatment with digoxin could reinduce clinically relevant RAI uptake in patients with metastasized RAI-refractory NMTC.
Methods: Eight patients with metastasized RAI-refractory NMTC were included between November 2022 and June 2023. Before treatment, a baseline [123I]NaI scintigraphy was performed. Thereafter, patients were treated with digoxin for 3 weeks. Starting doses depended on age and weight. For safety reasons, the usual therapeutic range was aimed for. After 1 week, the digoxin plasma concentration was measured, and the digoxin dose was adjusted if necessary. After 3 weeks of digoxin treatment, a second [123I]NaI scintigraphy was performed. RAI uptake was compared between the two scintigraphies.
Results: Seven patients completed the digoxin treatment and were evaluable. None of the seven patients showed clinically relevant RAI uptake after digoxin treatment. No digoxin-related serious adverse events occurred during this trial.
Conclusion: Contrary to results from preclinical trials, in this trial, 3 weeks of digoxin treatment did not reinduce RAI uptake in patients with NMTC. This highlights essential challenges regarding the approach toward optimization of studies aimed to restore the RAI uptake and its therapeutic efficacy through drug repurposing.
研究目的对放射性碘(RAI)难治的非髓性甲状腺癌(NMTC)患者预后较差。恢复摄取碘的能力(即所谓的再分化)的策略很有前景,但并非适用于所有患者。临床前研究表明,无论是在人类细胞系还是在小鼠模型中,强心甙地高辛都能恢复 RAI 的摄取。这项前瞻性单中心开放标签研究旨在探讨地高辛治疗是否能恢复转移性 RAI 难治性 NMTC 患者与临床相关的 RAI 摄取:在2022年11月至2023年6月期间,纳入了8名转移性RAI难治性NMTC患者。治疗前进行基线[123I]NaI-闪烁成像。此后,患者接受为期三周的地高辛治疗。起始剂量取决于年龄和体重。出于安全考虑,治疗剂量以通常的治疗范围为目标。一周后,测量地高辛血浆浓度,必要时调整地高辛剂量。地高辛治疗三周后,进行第二次[123I]NaI-闪烁成像。结果显示,7 名患者完成了地高辛治疗:结果:七名患者完成了地高辛治疗并接受了评估。结果:七名患者完成了地高辛治疗,并进行了评估。七名患者中没有一人在地高辛治疗后出现与临床相关的 RAI 摄取。试验期间未发生与地高辛相关的严重不良事件:结论:与临床前试验的结果相反,在这项试验中,三周的地高辛治疗并没有使 NMTC 患者重新摄取 RAI。这凸显了通过药物再利用来恢复 RAI 摄取及其疗效的优化研究方法所面临的重大挑战。
{"title":"Digoxin treatment does not reinduce radioiodine uptake in radioiodine refractory non-medullary thyroid carcinoma.","authors":"Pepijn van Houten, James Nagarajah, Janneke E W Walraven, Martin Jaeger, Adriana C H van Engen-van Grunsven, Johannes W Smit, Romana T Netea-Maier","doi":"10.1530/ETJ-24-0153","DOIUrl":"10.1530/ETJ-24-0153","url":null,"abstract":"<p><strong>Objective: </strong>Patients with non-medullary thyroid carcinoma (NMTC) that are refractory to radioactive iodine (RAI) have a poor prognosis. Strategies for restoring the ability to take up iodine, so-called redifferentiation, are promising but not suitable for all patients. Preclinical studies, in human cell lines just as in a murine model, have shown that the cardiac glycoside digoxin restored RAI uptake. This prospective single-center open-label study aimed to investigate whether treatment with digoxin could reinduce clinically relevant RAI uptake in patients with metastasized RAI-refractory NMTC.</p><p><strong>Methods: </strong>Eight patients with metastasized RAI-refractory NMTC were included between November 2022 and June 2023. Before treatment, a baseline [123I]NaI scintigraphy was performed. Thereafter, patients were treated with digoxin for 3 weeks. Starting doses depended on age and weight. For safety reasons, the usual therapeutic range was aimed for. After 1 week, the digoxin plasma concentration was measured, and the digoxin dose was adjusted if necessary. After 3 weeks of digoxin treatment, a second [123I]NaI scintigraphy was performed. RAI uptake was compared between the two scintigraphies.</p><p><strong>Results: </strong>Seven patients completed the digoxin treatment and were evaluable. None of the seven patients showed clinically relevant RAI uptake after digoxin treatment. No digoxin-related serious adverse events occurred during this trial.</p><p><strong>Conclusion: </strong>Contrary to results from preclinical trials, in this trial, 3 weeks of digoxin treatment did not reinduce RAI uptake in patients with NMTC. This highlights essential challenges regarding the approach toward optimization of studies aimed to restore the RAI uptake and its therapeutic efficacy through drug repurposing.</p>","PeriodicalId":12159,"journal":{"name":"European Thyroid Journal","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11378125/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141758069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-03Print Date: 2024-08-01DOI: 10.1530/ETJ-24-0125
Luca Persani, Patrice Rodien, Carla Moran, W Edward Visser, Stefan Groeneweg, Robin Peeters, Samuel Refetoff, Mark Gurnell, Paolo Beck-Peccoz, Krishna Chatterjee
Impaired sensitivity to thyroid hormones encompasses disorders with defective transport of hormones into cells, reduced hormone metabolism, and resistance to hormone action. Mediated by heritable single-gene defects, these rare conditions exhibit different patterns of discordant thyroid function associated with multisystem phenotypes. In this context, challenges include ruling out other causes of biochemical discordance, making a diagnosis using clinical features together with the identification of pathogenic variants in causal genes, and managing these rare disorders with a limited evidence base. For each condition, the present guidelines aim to inform clinical practice by summarizing key clinical features and useful investigations, criteria for molecular genetic diagnosis, and pathways for management and therapy. Specific, key recommendations were developed by combining the best research evidence available with the knowledge and clinical experience of panel members, to achieve a consensus.
{"title":"2024 European Thyroid Association Guidelines on diagnosis and management of genetic disorders of thyroid hormone transport, metabolism and action.","authors":"Luca Persani, Patrice Rodien, Carla Moran, W Edward Visser, Stefan Groeneweg, Robin Peeters, Samuel Refetoff, Mark Gurnell, Paolo Beck-Peccoz, Krishna Chatterjee","doi":"10.1530/ETJ-24-0125","DOIUrl":"10.1530/ETJ-24-0125","url":null,"abstract":"<p><p>Impaired sensitivity to thyroid hormones encompasses disorders with defective transport of hormones into cells, reduced hormone metabolism, and resistance to hormone action. Mediated by heritable single-gene defects, these rare conditions exhibit different patterns of discordant thyroid function associated with multisystem phenotypes. In this context, challenges include ruling out other causes of biochemical discordance, making a diagnosis using clinical features together with the identification of pathogenic variants in causal genes, and managing these rare disorders with a limited evidence base. For each condition, the present guidelines aim to inform clinical practice by summarizing key clinical features and useful investigations, criteria for molecular genetic diagnosis, and pathways for management and therapy. Specific, key recommendations were developed by combining the best research evidence available with the knowledge and clinical experience of panel members, to achieve a consensus.</p>","PeriodicalId":12159,"journal":{"name":"European Thyroid Journal","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11301568/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141534037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-02Print Date: 2024-08-01DOI: 10.1530/ETJ-23-0265
Julia A Baran, Mya Bojarsky, Stephen Halada, Julio C Ricarte-Filho, Amber Isaza, Aime T Franco, Lea F Surrey, Tricia Bhatti, Zubair Baloch, N Scott Adzick, Sogol Mostoufi-Moab, Ken Kazahaya, Andrew J Bauer
Objective: The American Thyroid Association (ATA) Pediatric Guidelines recommend selective, prophylactic central neck dissection (pCND) for patients with papillary thyroid carcinoma (PTC) based on tumor focality, tumor size, and the surgeon's experience. With the expansion of pre-surgical somatic oncogene testing and continued controversy over the benefits of pCND, oncogenic alteration data may provide an opportunity to stratify pCND. This study compared lymph node (LN) involvement in pediatric patients with PTC between tumors with low- and high-invasive-associated alterations to explore the potential utility of preoperative oncogenic alterations in the stratification of pCND.
Methods: This is retrospective cohort study of pediatric patients who underwent somatic oncogene testing post thyroidectomy for PTC between July 2003 and July 2022.
Results: Of 192 eligible PTC patients with postoperative somatic oncogene data, 19 tumors harbored somatic alterations associated with low-invasive disease (19/192, 10%), and 128 tumors harbored a BRAFV600E alteration (45/192, 23%) or an oncogenic fusion (83/192, 43%). Tumors with low-invasive alterations were less likely to present malignant preoperative cytology (2/18, 11%) than those with high-invasive alterations (97/124, 78%; P < 0.001). Twelve patients with low-invasive alterations had LNs dissected from the central neck (12/19, 63%) compared to 127 patients (127/128, 99%) with high-invasive alterations. LN metastasis was identified in two patients with low-invasive alterations (2/19, 11%) compared to 107 patients with high-invasive alterations (107/128, 84%; P < 0.001).
Conclusion: Pediatric patients with low-invasive somatic oncogenic alterations are at low risk for metastasis to central neck LNs. Our findings suggest that preoperative knowledge of somatic oncogene alterations provides objective data to stratify pediatric patients who may not benefit from pCND.
{"title":"Low-invasive somatic oncogenes and lymph node metastasis in pediatric papillary thyroid cancer: implications for prophylactic central neck dissection.","authors":"Julia A Baran, Mya Bojarsky, Stephen Halada, Julio C Ricarte-Filho, Amber Isaza, Aime T Franco, Lea F Surrey, Tricia Bhatti, Zubair Baloch, N Scott Adzick, Sogol Mostoufi-Moab, Ken Kazahaya, Andrew J Bauer","doi":"10.1530/ETJ-23-0265","DOIUrl":"10.1530/ETJ-23-0265","url":null,"abstract":"<p><strong>Objective: </strong>The American Thyroid Association (ATA) Pediatric Guidelines recommend selective, prophylactic central neck dissection (pCND) for patients with papillary thyroid carcinoma (PTC) based on tumor focality, tumor size, and the surgeon's experience. With the expansion of pre-surgical somatic oncogene testing and continued controversy over the benefits of pCND, oncogenic alteration data may provide an opportunity to stratify pCND. This study compared lymph node (LN) involvement in pediatric patients with PTC between tumors with low- and high-invasive-associated alterations to explore the potential utility of preoperative oncogenic alterations in the stratification of pCND.</p><p><strong>Methods: </strong>This is retrospective cohort study of pediatric patients who underwent somatic oncogene testing post thyroidectomy for PTC between July 2003 and July 2022.</p><p><strong>Results: </strong>Of 192 eligible PTC patients with postoperative somatic oncogene data, 19 tumors harbored somatic alterations associated with low-invasive disease (19/192, 10%), and 128 tumors harbored a BRAFV600E alteration (45/192, 23%) or an oncogenic fusion (83/192, 43%). Tumors with low-invasive alterations were less likely to present malignant preoperative cytology (2/18, 11%) than those with high-invasive alterations (97/124, 78%; P < 0.001). Twelve patients with low-invasive alterations had LNs dissected from the central neck (12/19, 63%) compared to 127 patients (127/128, 99%) with high-invasive alterations. LN metastasis was identified in two patients with low-invasive alterations (2/19, 11%) compared to 107 patients with high-invasive alterations (107/128, 84%; P < 0.001).</p><p><strong>Conclusion: </strong>Pediatric patients with low-invasive somatic oncogenic alterations are at low risk for metastasis to central neck LNs. Our findings suggest that preoperative knowledge of somatic oncogene alterations provides objective data to stratify pediatric patients who may not benefit from pCND.</p>","PeriodicalId":12159,"journal":{"name":"European Thyroid Journal","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11301529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141563078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hideyuki Imai, Natsuko Watanabe, Rei Hirose, Masakazu Koshibu, Masahiro Ichikawa, Akiko Sankoda, Shigenori Hiruma, Nami Suzuki, Masako Matsumoto, Miho Fukushita, Ai Yoshihara, Jaeduk Yoshimura Noh, Kiminori Sugino, Koichi Ito
Objective: There are few reports of subacute thyroiditis (SAT) during pregnancy. This study aimed to clarify the clinical characteristics of SAT in pregnant patients.
Methods and results: Seven patients diagnosed with SAT during pregnancy at our institution from January 2004 to December 2021 were identified, and their clinical findings were retrospectively examined. At SAT diagnosis, the median age was 34 [range 31-42] years, the median duration of pregnancy was 5 [4-24] weeks, and all patients had neck pain but no fever. On laboratory examination, median (range) free thyroxine, free triiodothyronine, and C-reactive protein levels were 2.66 (1.14-7.77) ng/dL, 7.1 (3.3-16.1) pg/mL, and 2.22 (0.42-5.79) mg/dL, respectively, and all patients had a hypoechoic lesion of the thyroid gland. Three patients (43%) were treated with steroids, and 3 patients (43%) received replacement therapy with levothyroxine for hypothyroidism following destructive thyroiditis. There were no pregnancy complications in any of the cases. These 7 patients (pregnancy group) were compared with 217 non-pregnant female patients (non-pregnancy group) aged 31 to 42 years who were diagnosed with SAT at our institution from 2016 to 2019. The frequency of body temperatures above 37°C was lower in the pregnancy group than in the non-pregnancy group (0% vs. 65%).
Conclusion: Patients who develop SAT during pregnancy may have less fever than non-pregnant patients with SAT. There were no pregnancy complications in the pregnancy group in this study. This suggests that adverse pregnancy outcomes may be avoided by appropriate management of SAT, including hypothyroidism after destructive thyroiditis.
{"title":"Subacute thyroiditis during pregnancy: clinical characteristics of seven cases.","authors":"Hideyuki Imai, Natsuko Watanabe, Rei Hirose, Masakazu Koshibu, Masahiro Ichikawa, Akiko Sankoda, Shigenori Hiruma, Nami Suzuki, Masako Matsumoto, Miho Fukushita, Ai Yoshihara, Jaeduk Yoshimura Noh, Kiminori Sugino, Koichi Ito","doi":"10.1530/ETJ-24-0128","DOIUrl":"https://doi.org/10.1530/ETJ-24-0128","url":null,"abstract":"<p><strong>Objective: </strong>There are few reports of subacute thyroiditis (SAT) during pregnancy. This study aimed to clarify the clinical characteristics of SAT in pregnant patients.</p><p><strong>Methods and results: </strong>Seven patients diagnosed with SAT during pregnancy at our institution from January 2004 to December 2021 were identified, and their clinical findings were retrospectively examined. At SAT diagnosis, the median age was 34 [range 31-42] years, the median duration of pregnancy was 5 [4-24] weeks, and all patients had neck pain but no fever. On laboratory examination, median (range) free thyroxine, free triiodothyronine, and C-reactive protein levels were 2.66 (1.14-7.77) ng/dL, 7.1 (3.3-16.1) pg/mL, and 2.22 (0.42-5.79) mg/dL, respectively, and all patients had a hypoechoic lesion of the thyroid gland. Three patients (43%) were treated with steroids, and 3 patients (43%) received replacement therapy with levothyroxine for hypothyroidism following destructive thyroiditis. There were no pregnancy complications in any of the cases. These 7 patients (pregnancy group) were compared with 217 non-pregnant female patients (non-pregnancy group) aged 31 to 42 years who were diagnosed with SAT at our institution from 2016 to 2019. The frequency of body temperatures above 37°C was lower in the pregnancy group than in the non-pregnancy group (0% vs. 65%).</p><p><strong>Conclusion: </strong>Patients who develop SAT during pregnancy may have less fever than non-pregnant patients with SAT. There were no pregnancy complications in the pregnancy group in this study. This suggests that adverse pregnancy outcomes may be avoided by appropriate management of SAT, including hypothyroidism after destructive thyroiditis.</p>","PeriodicalId":12159,"journal":{"name":"European Thyroid Journal","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Highly selective RET inhibitor selpercatinib has demonstrated notable efficacy in advanced/progressive RET-mutant medullary thyroid cancer (MTC) patients. However, despite a more tolerable toxicity profile than multikinase inhibitors, peculiar adverse events (AEs) have been described. Obliterative bronchiolitis (OB) is a respiratory disease characterized by inflammation and fibrosis in small conducting airways. We evaluated a 70 years-old man with advanced RET-mutant MTC who developed OB during treatment with selpercatinib. Radiological features of OB occurred early and persisted during selpercatinib treatment, with a waxing and waning pattern. Notably, a partial response of MTC was achieved during the treatment and selpercatinib was never reduced or interrupted. The almost complete absence of symptoms and the fluctuating trend, without specific treatment for OB, suggested that it is necessary to carefully evaluate the risks mediated by this AE with the risks of modifying or discontinuing the anti-cancer therapy.
{"title":"Fluctuating obliterative bronchiolitis in RET-mutant medullary thyroid cancer patient treated with selpercatinib.","authors":"Carla Gambale, Alessandro Prete, Chiara Romei, Alessandro Celi, Rossella Elisei, Antonio Matrone","doi":"10.1530/ETJ-24-0189","DOIUrl":"10.1530/ETJ-24-0189","url":null,"abstract":"<p><p>Highly selective RET inhibitor selpercatinib has demonstrated notable efficacy in advanced/progressive RET-mutant medullary thyroid cancer (MTC) patients. However, despite a more tolerable toxicity profile than multikinase inhibitors, peculiar adverse events (AEs) have been described. Obliterative bronchiolitis (OB) is a respiratory disease characterized by inflammation and fibrosis in small conducting airways. We evaluated a 70 years-old man with advanced RET-mutant MTC who developed OB during treatment with selpercatinib. Radiological features of OB occurred early and persisted during selpercatinib treatment, with a waxing and waning pattern. Notably, a partial response of MTC was achieved during the treatment and selpercatinib was never reduced or interrupted. The almost complete absence of symptoms and the fluctuating trend, without specific treatment for OB, suggested that it is necessary to carefully evaluate the risks mediated by this AE with the risks of modifying or discontinuing the anti-cancer therapy.</p>","PeriodicalId":12159,"journal":{"name":"European Thyroid Journal","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alison-Michelle Naujack, Christin Krause, Jan H Britsemmer, Natalie Taege, Jens Mittag, Henriette Kirchner
Objective: Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by inflammation, fibrosis and accumulation of fatty acids in the liver. MASH disease progression has been associated with reduced thyroid hormone (TH) signalling in the liver, including reduced expression of deiodinase type I (DIO1) and TH receptor beta (THRB). However, the underlying mechanisms mediating these effects remain elusive. Here, we hypothesized, that epigenetic mechanisms may be involved in modulating hepatic TH action.
Methods: Liver samples from patients with and without MASH were analyzed by qRT-PCR and correlated with clinical parameters. Luciferase reporter assays and overexpression of miRNA in HepG2-cells were used to validate functional binding of miRNA to predicted targets. DNA-methylation was analyzed by bisulfite-pyrosequencing.
Results: miR-34a-5p was upregulated in MASH patients and correlated positively with clinical parameters of MASH. Using in silico and in vitro analysis we demonstrate that miR-34a-5p is capable of targeting several modulators of local hepatic TH action, as evidenced by functional binding of miR-34a-5p to the seed sequence in the THRB and DIO1 genes. Consequently, overexpression of miR-34a-5p in HepG2-cells reduced the expression of THRA, THRB, DIO1 and SLC10A1, thus potentially mediating an acquired hepatic resistance to TH in MASH. As additional regulatory mechanism, DNA-methylation of THRB intron 1 was increased in MASH and negatively correlated with THRB expression.
Conclusion: miR-34a-5p constitutes a possible epigenetic master regulator of hepatic TH action, which together with THRB specific DNA-methylation could explain a possible developing TH resistance in the liver during MASH progression on the molecular level.
{"title":"Epigenetic regulation of thyroid hormone action in human metabolic dysfunction associated steatohepatitis.","authors":"Alison-Michelle Naujack, Christin Krause, Jan H Britsemmer, Natalie Taege, Jens Mittag, Henriette Kirchner","doi":"10.1530/ETJ-24-0080","DOIUrl":"10.1530/ETJ-24-0080","url":null,"abstract":"<p><strong>Objective: </strong>Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by inflammation, fibrosis and accumulation of fatty acids in the liver. MASH disease progression has been associated with reduced thyroid hormone (TH) signalling in the liver, including reduced expression of deiodinase type I (DIO1) and TH receptor beta (THRB). However, the underlying mechanisms mediating these effects remain elusive. Here, we hypothesized, that epigenetic mechanisms may be involved in modulating hepatic TH action.</p><p><strong>Methods: </strong>Liver samples from patients with and without MASH were analyzed by qRT-PCR and correlated with clinical parameters. Luciferase reporter assays and overexpression of miRNA in HepG2-cells were used to validate functional binding of miRNA to predicted targets. DNA-methylation was analyzed by bisulfite-pyrosequencing.</p><p><strong>Results: </strong>miR-34a-5p was upregulated in MASH patients and correlated positively with clinical parameters of MASH. Using in silico and in vitro analysis we demonstrate that miR-34a-5p is capable of targeting several modulators of local hepatic TH action, as evidenced by functional binding of miR-34a-5p to the seed sequence in the THRB and DIO1 genes. Consequently, overexpression of miR-34a-5p in HepG2-cells reduced the expression of THRA, THRB, DIO1 and SLC10A1, thus potentially mediating an acquired hepatic resistance to TH in MASH. As additional regulatory mechanism, DNA-methylation of THRB intron 1 was increased in MASH and negatively correlated with THRB expression.</p><p><strong>Conclusion: </strong>miR-34a-5p constitutes a possible epigenetic master regulator of hepatic TH action, which together with THRB specific DNA-methylation could explain a possible developing TH resistance in the liver during MASH progression on the molecular level.</p>","PeriodicalId":12159,"journal":{"name":"European Thyroid Journal","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hyun-Jin Lee, Young-Sool Hah, So Young Cheon, Seong Jun Won, Chae Dong Yim, Somi Ryu, Seong-Jun Lee, Ji Hyun Seo, Jung Je Park
Objective: This study examined the effect of Sirtuin 4 (Sirt4), a NAD+-dependent deacetylase, on the proliferation and progression of papillary thyroid carcinoma (PTC).
Methods: Data from The Cancer Genome Atlas (TCGA) were analyzed to identify Sirt4 expression in thyroid cancer. Subsequently, the correlation between Sirt4 expression and clinical characteristics was examined in 205 PTC tissue samples. In vitro assays using three human thyroid cancer cell lines (B-CPAP, TPC-1, and SNU-790) were conducted to assess the effects of regulated Sirt4 expression on cell growth, apoptosis, invasion, and migration. Furthermore, in vivo experiments were performed in a xenograft mouse model.
Results: GEO and TCGA data indicated that Sirt4 expression is lower in thyroid cancer and Sirt4 downregulation is associated with poor overall survival. In our PTC tissues, positive Sirt4 expression was associated with decreased extracapsular extension. In in vitro experiments using three human thyroid cancer cell lines, overexpression of Sirt4 decreased cell survival, clonogenic potential, and invasion and migratory capabilities, as well as inducing apoptosis and increasing reactive oxygen species levels. Sirt4 overexpression upregulated E-cadherin and downregulated N-cadherin, suggesting its potential involvement in the regulation of epithelial-mesenchymal transition. These findings were confirmed in vivo using a xenograft mouse model.
Conclusion: This study provides novel insight into the potential contribution of Sirt4 to regulation of the pathological progression of PTC. The data suggest that Sirt4 plays a tumor-suppressive role in PTC by inhibiting growth, survival, and invasive potential. Future research should investigate the molecular mechanisms underlying these effects of Sirt4.
{"title":"Decreased Sirtuin 4 Levels Promote Cellular Proliferation and Invasion in Papillary Thyroid Carcinoma.","authors":"Hyun-Jin Lee, Young-Sool Hah, So Young Cheon, Seong Jun Won, Chae Dong Yim, Somi Ryu, Seong-Jun Lee, Ji Hyun Seo, Jung Je Park","doi":"10.1530/ETJ-24-0079","DOIUrl":"https://doi.org/10.1530/ETJ-24-0079","url":null,"abstract":"<p><strong>Objective: </strong>This study examined the effect of Sirtuin 4 (Sirt4), a NAD+-dependent deacetylase, on the proliferation and progression of papillary thyroid carcinoma (PTC).</p><p><strong>Methods: </strong>Data from The Cancer Genome Atlas (TCGA) were analyzed to identify Sirt4 expression in thyroid cancer. Subsequently, the correlation between Sirt4 expression and clinical characteristics was examined in 205 PTC tissue samples. In vitro assays using three human thyroid cancer cell lines (B-CPAP, TPC-1, and SNU-790) were conducted to assess the effects of regulated Sirt4 expression on cell growth, apoptosis, invasion, and migration. Furthermore, in vivo experiments were performed in a xenograft mouse model.</p><p><strong>Results: </strong>GEO and TCGA data indicated that Sirt4 expression is lower in thyroid cancer and Sirt4 downregulation is associated with poor overall survival. In our PTC tissues, positive Sirt4 expression was associated with decreased extracapsular extension. In in vitro experiments using three human thyroid cancer cell lines, overexpression of Sirt4 decreased cell survival, clonogenic potential, and invasion and migratory capabilities, as well as inducing apoptosis and increasing reactive oxygen species levels. Sirt4 overexpression upregulated E-cadherin and downregulated N-cadherin, suggesting its potential involvement in the regulation of epithelial-mesenchymal transition. These findings were confirmed in vivo using a xenograft mouse model.</p><p><strong>Conclusion: </strong>This study provides novel insight into the potential contribution of Sirt4 to regulation of the pathological progression of PTC. The data suggest that Sirt4 plays a tumor-suppressive role in PTC by inhibiting growth, survival, and invasive potential. Future research should investigate the molecular mechanisms underlying these effects of Sirt4.</p>","PeriodicalId":12159,"journal":{"name":"European Thyroid Journal","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141909833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}